Effects of CYP1A2 on Disposition of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-Pentachlorodibenzofuran, and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in CYP1A2 Knockout and Parental (C57BL/6N and 129/Sv) Strains of Mice

• Published in: Toxicology and applied pharmacology 1999-08, Vol.159 (1), p.52-64
• Main Authors: Diliberto, Janet J., Burgin, Deborah E., Birnbaum, Linda S.
• Format: Article
• Language: English
• Subjects: Animals; Benzofurans - pharmacokinetics; Benzofurans - urine; Biological and medical sciences; Body Weight - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; Cytochrome P-450 CYP1A2 - physiology; Environmental Pollutants - pharmacokinetics; Environmental Pollutants - urine; Feces - chemistry; Liver - chemistry; Medical sciences; Mice; Mice, Inbred Strains - genetics; Mice, Knockout; Organ Size - drug effects; Polychlorinated Biphenyls - pharmacokinetics; Polychlorinated Dibenzodioxins - pharmacokinetics; Tissue Distribution; Toxicology; Various organic compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1999.8720

TCDD is the prototype and most potent member of the highly lipophilic polyhalogenated aromatic hydrocarbons (PHAHs), which are persistent and ubiquitous environmental contaminants. In both acute and subchronic animal studies, there is a specific accumulation of TCDD in liver greater than in adipose tissue. The inducible hepatic binding protein responsible for this hepatic sequestration of TCDD and its congeners has been shown by our laboratory to be CYP1A2 (J. J. Diliberto, D. Burgin, and L. S. Birnbaum, 1997, Biochem. Biophys. Res. Commun. 236, 431–433). The present study was conducted using knockout (KO) mice lacking expression of CYP1A2 (CYP1A2−/−) in order to investigate the role of CYP1A2 gene on the disposition of TCDD, 4-PeCDF (a dioxin-like PHAH), and PCB 153 (a nondioxin-like PCB) in KO (CYP1A2−/−) mice and age-matched parental mice strains (C57BL/6N: CYP1A2+/+, Ahb/b and 129/Sv: CYP1A2+/+, Ahd/d). Mice were dosed (25 μg [3H]TCDD/kg, 300 μg [14C]4-PeCDF/kg, or 35.8 mg [14C]PCB 153/kg bw in a corn oil vehicle) orally and terminated after 4 days. Residues of administered compounds in collected tissues and daily excreta were quantitated using 3H or 14C activity. Results demonstrated differential effects in disposition for the various treatments within the three genetically different groups of mice. In KO mice, TCDD, 4-PeCDF, and PCB 153 had very little hepatic localization of chemical, and the major depot was adipose tissue. In contrast, parental strains demonstrated hepatic sequestration of TCDD and 4-PeCDF, whereas disposition of PCB 153 in parental strains was similar to that in KO mice. Another difference between KO mice and parental strains was the enhanced urinary excretion of 4-PeCDF. This study demonstrates the importance of CYP1A2 in pharmacokinetic behavior and mechanistic issues for TCDD and related compounds.